We propose the existence in mammalian cells of at least two distinct receptors for 3 prostaglandins linked to adenylate cyclase. The objective of the research proposed is to test this hypothesis. Thus, we intend to conduct a pharmacological characterization of the response to prostaglandins of a variety of cells in culture and of human and rat adipocytes, platelets and lymphocytes as well as in frog and turkey erythrocytes. The response measured will be the formation of cyclic AMP in intact cells using methods previously established in this laboratory. Once the classes of PGE receptors are delineated in terms of structure-activity relationships for both agonists and antagonists we will conduct a comparative analysis of the factors that influence the response of the different receptor-cyclase systems to prostaglandins. Namely, 1) Do all classes of PGE-receptor exhibit tachyphylaxis to continued exposure to PGE?; what is the mechanism by which loss of responiveness occurs?; are intermediates of PGE2 synthesis (endoperoxides, thromboxanes) involved? 2) What is the identity and involvement of a protein in serum in the effect of glucorcorticoids to enhance the responsiveness of certain cells to PGE? 3) How do the properties of different classes of PGE-receptor-linked adenylate cyclases compare when examined in membrane preparations? The identification and characterization of different classes of adenylate cyclase-linked receptors for 3 prostaglandins should provide the basis for a more coherent interpretation of the effects of prostaglandins on physiological function.